Histamine, a mediator of inflammation and regulator of innate and adaptive immune responses, plays a significant role in the pathogenesis of experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS). Histamine exerts its effect through four G-protein coupled receptors (GPCRs) designated histamine H1, H2, H3, and H4 receptor (H1R, H2R, H3R, and H4R). H1R is expressed in chronic MS plaques and MS patients receiving the H1R antagonist hydroxyzine remain stable or improve neurologically. Moreover, epidemiological data indicate that H1R antagonist use is associated with decreased MS risk. In MS and EAE histamine is viewed primarily as a mediator of inflammation due to its effect on the vasculature and blood brain barrier permeability. However, data in histamine- and histamine receptor- (HR) deficient mice indicate that histamine also plays a role in regulating encephalitogen-specific T-cell effector responses. We published that compared to wild-type mice, H1RKO mice develop less severe EAE and Th2-like anti-MOG35-55 CD4 T-cell responses. We now show that the H1R regulates IFN3 production by CD4 effector T-cells as a result of direct signaling during their initial activation. Additionally, we present data showing that all four HRs play a role in EAE. Moreover, in addition to expressing the H1R naive CD4 T-cells express the H2R and H4R but not the H3R, and upon activation down regulate the expression of all three HR types; however, CD4 memory T-cells gain expression of the H3R. Our overall working hypothesis is that direct HR signaling during activation of naive and memory CD4 T-cells regulates effector responses. In this application we propose to: 1) delineate the H1R signaling pathway regulating IFN3 secretion in CD4 T-cells and test the hypothesis that H1R signaling also regulates susceptibility to spontaneous EAE in (B6.TgTcrMOG W B6.TgIghMOG) F1 hybrid mice; 2) test the hypothesis that H2R and H4R signaling in naive CD4 T-cells directly regulate encephalitogen-specific T-cell effector responses, and 3) test the hypothesis that H3R signaling regulates MOG35-55-specific CD4 memory T-cell responses. Delineating the CD4 effector T-cell responses regulated by HRs in EAE may aid in the development of new strategies for the treatment of MS and modification of primary and anamnestic CD4 T-cell responses in general. In this regard, GPCRs are one of the most tractable set of targets for the development of clinically effective, small molecule pharmaceuticals. Of the drugs used clinically in man ~50% target GPCRs.